Tumour necrosis factor‐α polymorphism and the HLA‐Cw*0602 allele in psoriatic arthritis

Objectives. To investigate polymorphisms in the genes for tumour necrosis factor a (TNFA), interleukin 10 (IL10) and tumour necrosis factor receptor II (TNFRII ) in patients with psoriatic arthritis (PsA) and their relationship to the HLA-Cw*0602 allele and to the ages at onset of psoriasis and arthritis and the pattern of joint involvement. Methods. One hundred and twenty-four well-characterized patients with PsA were studied. Controls were 101 cadaveric organ donors. All were genotyped for single-nucleotide polymorphisms in TNFA (positions 2308, 2238, + 488), IL10 (21082, 2819, 2592) and in the 39-untranslated region of TNFRII (+1663, +1668, +1690). The HLA-Cw*0602 allele was detected by polymerase chain reaction-based techniques. The frequencies of the respective variants were compared between patients and controls and in relation to the ages at onset of psoriasis and arthritis, to clinical subsets of the disease and to the presence of erosions. Results. HLA-Cw*0602 was significantly increased in frequency in PsA (40 vs 26%; P< 0.05) and was associated with younger age of onset of psoriasis (P< 0.05). There was no significant increase in any of the polymorphisms studied within TNFA, IL10 or TNFRII in the total PsA group. Although the frequency of TNFA allele 2238A was not increased in the total PsA group or in patients with a younger age of onset of psoriasis, TNFA allele 2238A was absent in the spondyloarthritis group and increased in frequency in patients with peripheral polyarthritis. However, these latter findings could be explained by linkage disequilibrium as all TNFA 2238A alleles (23u23) in patients with PsA were HLA-Cw*0602-positive (P< 0.0001). Conclusions. An association between young age of onset of psoriasis and HLA-Cw*0602 is confirmed in patients with PsA. The uncommon TNFA 2238A allele is strongly linked to HLA-Cw*0602 and as such is associated with the development of peripheral polyarthritis rather than spondylitis. Further investigation of possible HLA-Cw*0602 linked genes in PsA is warranted. Psoriatic arthritis (PsA) is an inflammatory disorder of unknown aetiology that may affect the synovium and enthesis of peripheral and axial joints, and occurs in 7‐42% of patients with psoriasis. The prevalence of PsA among first-degree relatives of patients with PsA is 5.5% compared with an estimated 0.1% in the normal population w1x. Significant gene linkage with psoriasis has been found on chromosomes 6p 17q, 4q and 1q w2, 3x. The main MHC class I allele that has been associated with susceptibility to psoriasis is HLA-Cw*0602 w4, 5x; there are other, weaker associations with HLA-B alleles, reflecting linkage disequilibrium. However, MHC class I alleles are involved in the regulation of NK cells, which have no proven role in psoriasis. There are weaker associations between PsA and MHC class II genes, such as HLA-DR7 w6, 7x. A possible explanation is that there may be several non-HLA genes in the MHC region, including the gene for psoriasis anduor PsA. Tumour necrosis factor a (TNF-a) is a potent proinflammatory immunomodulatory cytokine that is produced by monocytesumacrophages. It plays a central role in the initiation and regulation of the immune response. The biological action of TNF-a is regulated through two receptors, TNF-RI and TNF-RII w8x and down-regulated through anti-inflammatory cytokines